Abstract The Bruker Avance I-600 MHz NMR spectrometer, which is the key and only active 600MHz instrument at the Cleveland Center for Membrane and Structural Biology (CCMSB), has been dysfunctional for the past several months. The symptoms include frequent interruption of the experiments followed by the cryoprobe warm-up. The cryoprobe, after many such interruptions and warm-ups, has also been damaged with ~40% sensitivity drop. Routine 3D triple resonance NMR experiments cannot be performed effectively on this instrument any more. Our repair team comprising expert from Bruker BioSpin has made tremendous effort to troubleshoot the problems by replacing numerous parts without success, leading to the conclusion that the console of this particular instrument, which has been continuously running for nearly 13 years, has reached its lifetime and needs to be upgraded. In the past 13 years, this instrument has acted as a workhorse for a large number of biomedically important projects as supported by dozens of NIH grants, and thus has significantly contributed to the life science and regional economy. Here we request funds to upgrade the instrument by purchasing a new console equipped with a new state-of-the-art TCI cryoprobe. The upgrade is not only essential to allow the investigators to continue their research but also will enhance their capacity to carry out novel projects due to the new features in the upgraded instrument including substantially enhanced sensitivity, non-linear sampling, which dramatically reduce the NMR acquisition time by a factor of 2-5, and 19F detecting capability, which allows the direct characterization of 19F-labeled drugs and macromolecules in vitro and in cells. The projects of the investigators range from studies of unresolved mechanisms central to development, physiology, pharmacology. Translational components exist for many of the NIH-supported projects as exemplified by the development of inhibitors for inflammatory diseases, design of novel thermostable and long-lasting insulin analogs, understanding and manipulating cell signaling in carcinogenesis, and protein misfolding in Alzheimer's disease and prions. The upgraded instrument will also play a direct role in training students and fellows creating the critical mass of expertise in the region, thereby promoting the development of cutting edge biological research and associated high technology industry in the mid-west.